Adamalysin (“ADAM”) is a subfamily of enzymes in the zinc metalloendopeptidases. ADAMs contain a disintigrin domain in addition to a metalloproteinase-like domain. At least twenty-three distinct ADAMs have been identified thus far.
ADAM-17, also known as tumor necrosis factor-alpha converting enzyme (hereinafter “TACE”), is the most well known ADAM. TACE is responsible for cleavage of cell bound tumor necrosis factor-alpha (“TNF-α”). TNF-α is implicated in many infectious and autoimmune diseases. Moreover, TNF-α is the prime mediator in the inflammatory response seen in sepsis and septic shock. There are two types of TNF-α, a type II membrane protein of relative molecular mass of 26 kD, and a soluble 17 kD form generated from the cell bound protein by specific proteolytic cleavage. The soluble 17 kD form of TNF-α is released by the cell and is associated with the deleterious effets of TNF-α. This form of TNF-α is also capable of acting at sites distant from the site of synthesis. Thus, inhibitors of TACE prevent the formation of soluble TNF-α and thus prevent the deleterious effects of the soluble factor.
Although a variety of TACE inhibitors are known in the art, many of these molecules are peptidic and peptide-like which suffer from bioavailability and pharmacokinetic problems. In addition, many of these molecules are non-selective, being potent inhibitors of matrix metalloproteinases and, in particular, MMP-1. Inhibition of MMP-1 (collagenase-1) has been postulated to cause joint pain in clinical trials of MMP inhibitors.
Thus, there is a need for TACE inhibitors that are selective, orally bioavailable, non-peptidic for the treatment of diseases associated with TNF-α.